Use of 7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-quinolone carboxylic acid and naphthyridone carboxylic acid derivatives for treating Helicobacter pylori infections and the gastroduodenal diseases associated therewith

ABSTRACT

The invention relates to the use of quinolone- and naphthyridonecarboxylic acid derivatives which are substituted in position 7 by a 1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]oct-7-yl radical, and of their salts for the therapy of  Helicobacter pylori  infections and associated gastroduodenal disorders.

This application is a 371 of PCT/EP97/06751 filed on Dec. 3, 1997.

The invention relates to the use of quinolone- andnaphthyridonecarboxylic acid derivatives which are substituted inposition 7 by a 1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-ylradical, and of their salts for the therapy of Helicobacter pyloriinfections and associated gastroduodenal disorders.

In the years following the rediscovery of Helicobacter pylori (H.pylori; old name Campylo-bacter pylori) by Warren and Marshall in 1983,the pathophysiological ideas on the genesis of gastro-duodenal disordersin man were developed further in a fundamental way.

H. pylori is considered to be the cause of type B gastritis and seems toplay a causative part in the perpetuation of peptic ulcers.Epidemiological and pathological investigations likewise indicate aconnection between the long-term colonization of the mucosa of thestomach by the bacterium and the formation of certain forms of stomachcarcinoma. Because of this, H. pylori was, in 1994, classed as acarcinogen of the first order (most dangerous cancer-causing category).A rare form of stomach cancer, MALT lymphoma (mucosa-associated lymphoidtissue) appears likewise frequently to be caused by the germ. Indeed, ininitial casuistries, after H. pylori eradication, not only the reactiveinfiltrates disappeared, but even some of the MALT lymphomas of lowmalignancy. A connection with Ménétrier's syndrome is also beingdiscussed. The role of H. pylori in functional gastropathy (nonulcerousdyspepsia) is still unclear.

Various epidemiological studies reach the conclusion that approximatelyhalf of the population of the world is infected with the bacterium. Thelikelihood of colonization of the stomach by Helicobacter increases as afunction of age. The optimum adaptation of Helicobacter to the livingconditions in the unusual, low-competition habitat of the stomach seemsto be the precondition for successful establishment of the chronicinfection and for the wide distribution of this pathogenic species.

The pathogens are, with their flagella, not only highly mobile in liquidmedia but also in the viscous mucous of the mucosa of the stomach, theyadhere to the epithelial cells of the stomach and they multiply best atan oxygen content of 5%, as is prevalent in the mucous of the stomachwall. Moreover, the bacteria produce large amounts of the enzyme ureasewhich cleaves urea into ammonia and carbon dioxide. The “cloud ofammonia” which is formed possibly assists the bacteria in neutralizingthe acidic medium in the microenvironment, resulting in protectionagainst the aggressive stomach acid.

Peptic Ulcers

The introduction of the histamine H₂-receptor antagonists in the 1970swas a milestone in the therapy of peptic ulcers. World-wide, thefrequency of surgical interventions for the treatment of the ulcerdecreased dramatically. This principle of the acid blockade was improvedeven more by the development of the more strongly effective proton pumpinhibitors.

However, the antacid therapy has a causal effect—i.e. by disinfectanttreatment—only on the symptoms of the ulcer, not on the natural cause ofthe disease which is characterized by the occurrence of relapses. Thisis because virtually all ulcus duodeni patients and a predominantmajority of the patients suffering from ulcus ventriculi have an H.pylori infection of the stomach and therefore suffer from infectiousdiseases. Only ulcerations caused by nonsteroidal antiphlogistics arenot associated with an H. pylori infection.

Thus, according to the recommendations of a consensus conference whichwas organized by the American National Institute of Health (NIH) in1994, all patients suffering from peptic ulcers should, in the case of apositive germ test, undergo eradication therapy directed against H.pylori (NIH Consensus Statement 1: 1-23; 1994). The arguments in favourof this came from controlled therapy studies which showed that, aftersuccessful germ eradication, the ulcer relapse rates decreasedramatically (0%-29% versus 61%-95%).

H. pylon Therapy

In practice, the current eradication of H. pylori is not particularlysimple. There is no simple and nevertheless reliably effective therapy.The germ is located under the layer of mucous, where it is wellprotected and difficult to attack.

In vitro, H. pylori shows sensitivity towards numerous antibiotics.However, these antibiotics are, as a monotherapy, not effective in vivo.They include, inter alia, penicillin, amoxicillin, tetracycline,erythromycin, ciprofloxacin, metronidazole and clarithromycin. Likewise,bismuth salts and to a lesser extent even proton pump inhibitors(omeprazole, lansoprazole) have antibacterial activity in vitro, but notin vivo.

Among all the therapy modalities used hitherto for eradicating H.pylori, to date only the triple therapies below are sufficientlyeffective:

1. classic bismuth triple therapy (bismuth salt plus two antibiotics)and

2. modified triple therapy (antacid plus two antibiotics).

However, these regimes are complicated eradication methods with poorcompliance which may in up to 35% of all cases be associated with sideeffects (stomach aches, sickness, diarrhoea, a dry mouth, impairment oftaste and allergic skin reactions, etc.). This makes a broader use moredifficult. Another great disadvantage is the large number of medicamentswhich have to be taken every day (12-16 tablets/day). This isparticularly pronounced in the quadruple therapy where an acid secretioninhibitor is administered simultaneously with the classic tripletherapy.

However, the dual therapy (combination of amoxicillin with omeprazole),which is better tolerated and is propagated in Germany, has only a lowefficacy and even seems to fail substantially in the case of patientswho have been pre-treated with omeprazole and in the case of smokers.

The antibiotic components which are generally administered in tripletherapies are amoxicillin, nitroimidazole compounds (metronidazole,tinidazole), tetracycline and, more recently, macrolides(clarithromycin) [in 3-4 partial doses].

Throughout the world, eradication rates of 70-90% are achieved. However,this eradication success can be influenced by a variety of factors:

1. Primarily, mention has to be made of the resistance of the germ(developing countries: up to 60%, Germany: up to 10%) towardsmetronidazole, the antibiotic which is most frequently used in thetriple therapy. In the treatment with Clarithromycin, reference islikewise made to the disadvantage of a resistance development of up to10%.

2. Another factor which has to be mentioned is the abovementionedcompliance of the patients.

Animal Model

An H. felis mouse model has been described as a suitable animal model[A. Lee et al., Gastroentrology 99: 1315-1323 (1990)] and we modifiedthis model in such a way that it is highly suitable for the screeningand the comparative assessment of the abovementioned compounds.

In spite of considerable morphological differences, the corkscrew-like,urease-forming bacterium H. felis is very closely related to H. pylori.H. felis is a natural inhabitant of the mucosa of the stomach of dogsand cats. After oral inoculation, the pathogens also colonize thestomach of mice, in a similar manner to that in which H. pyloricolonizes the stomach of humans. The established chronic long-terminfection leads to active gastritis in germ-free mice and induces acorresponding immune response.

The therapeutic efficacy of test samples determined in the H. felismouse model is considered to be very predictive for the correspondingclinical activity.

In spite of very good in vitro activity of antibiotics (for exampleAmoxicillin or erythromycin) against H. pylori, these do not show anysignificant clinical therapeutic effect after having been administeredin monotherapy. This fact is also represented by the H. felis mousemodel. Correspondingly, the clinically accepted eradicative effect ofthe classic triple therapy could also be confirmed in the H. felis mousemodel.

Antibacterially effective7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)quinolone- and-naphthyridonecarboxylic acid derivatives have already been disclosed inEuropean Patent Application 589 318 (Bayer). The surprising activity ofsuch compounds for controlling Helicobacter spp. has hitherto not beendisclosed. Furthermore, European Patent Application 671 391 (Bayer)discloses that7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolonecarboxylicacid is likewise effective against H. pylori. However, this activity isrelatively low. The 5-ethinyl derivative, which is also described inthis application, has been found to be unstable and therefore unsuitablefor therapeutic use. Japanese Patent Application JP 8048629 (Dainippon)discloses that compounds such as8-chloro-1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (BAY Y 3118) have antibacterial activity against H. pylori. It isalso known that a number of highly active quinolones, such as, forexample, ciprofloxacin, lomefloxacin or ofloxacin (Journal ofAntimicrobial Chemotherapy 22, 631-636 [1988], Antimicrobial Agents andChemotherapy, 33, 108-109 [1989]), exhibit in vitro activity againstHelicobacter spp. in the animal model (H. felis, mouse), however, it wasfound that these clinically used, antibacterially active quinolones arenot capable of eradicating the germ. It is also not possible to achieveeradication of H. felis in the mouse model by monotherapeutic treatmentwith highly active quinolones which have hitherto not been introducedinto the market, such as, for example, with the abovementioned BAY Y3118. The use of trovafloxacin or its derivatives in combination withother antibiotics, such as amoxicillin or tetracyclines, or proton pumpinhibitors, such as Omeprazole, for the therapy of H. pylori isdescribed in the Patent Applications EP 676 199 and GB 2 289 674(Pfizer). It was an object of the present invention to providewell-tolerated active compounds which are capable of eradicating thishighly specialized bacterium by simple monotherapy.

It has now been found that the compounds of the formula (I)

T—Q  (I),

in which

Q represents a radical of the formulae

 in which

R¹ represents alkyl having 1 to 4 carbon atoms which is optionally mono-to trisubstituted by halogen or hydroxyl, alkenyl having 2 to 4 carbonatoms, cycloalkyl having 3 to 6 carbon atoms which is optionallysubstituted by 1 or 2 fluorine atoms, bicyclo[1.1.1]pent-1-yl,1,1-dimethylpropargyl, 3-oxetanyl, methoxy, amino, methylamino,dimethylamino, phenyl which is optionally mono- or disubstituted byhalogen, amino or hydroxyl, isoxazolyl, thiadiazolyl,

R² represents hydroxyl, alkoxy having 1 to 4 carbon atoms which isoptionally substituted by hydroxyl, methoxy, amino, dimethylamino orethoxycarbonyl, benzyloxy, allyloxy, propargyloxy or(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyloxy, acetoxymethyloxy,pivaloyloxymethyloxy, 5-indanyloxy, phthalidinyloxy,3-acetoxy-2-oxobutyloxy, nitromethyl or dialkoxycarbonylmethyl having 1to 2 carbon atoms in each alkyl moiety,

R³ represents hydrogen, amino, hydroxyl, methyl or halogen,

R⁹ represents hydrogen or optionally methoxy-, hydroxyl- orhalogen-substituted alkyl having 1 to 3 carbon atoms,

R¹¹ represents hydrogen, CH₃ or CH₂F,

A represents N or C—R⁷ in which

R⁷ represents hydrogen, halogen, CF₃, OCH₃, OCHF₂, CH₃, CN, CH═CH₂ orC≡CH or else together with R¹ may form a bridge of the structure—*O—CH₂—CH—CH₃, —*S—CH₂—CH₂—, —*S—CH₂—CH—CH₃, —*CH₂—CH₂—CH—CH₃ or—*O—CH₂—N—R⁸ where the atom marked with * is attached to the carbon atomof A and in which

R⁸ represents hydrogen, methyl or formyl,

B represents N, C—H, C—F, C—Cl, C—NO₂, C—NH₂,

D represents N or C—R¹⁰ in which

R¹⁰ represents hydrogen, halogen, CF₃, OCH₃, OCHF₂ or CH₃ or elsetogether with R⁹ may form a bridge of the structure —*O—CH₂—, —*NH—CH₂—,—*N(CH₃)—CH₂—, —*N(C₂H₅)—CH₂—, —*N(c—C₃H₅)—CH₂—or —*S—CH₂— where theatom marked with * is attached to the carbon atom of D,

Y represents hydrogen or together with R² may form a bridge of thestructure —*S—NH— where the atom marked with * represents Y, and

T represents a radical of the formula

 in which

R⁴ represents H, CH₃, C₂H₅, optionally amino-substituted acyl having 1to 5 carbon atoms, alkoxycarbonyl, aminocarbonyl, alkylthiothiocarbonyland dialkoxyphosphoryl having 1 to 4 carbon atoms in the alkyl moiety,

R⁵ represents H, CH₃, C₂H₅ and

R⁶ represents H, CH₃,

and their pharmaceutically useful hydrates and acid addition salts andthe alkali metal, alkaline earth metal, silver and guanidinium salts ofthe parent carboxylic acids have high antibacterial activity againstHelicobacter spp. and can be employed for eradicating this pathogen.

Preference is given to the compounds of the formula (I) in which

Q represents a radical of the formula

 in which

R¹ represents alkyl having 1 to 4 carbon atoms which is optionally mono-to trisubstituted by fluorine, represents vinyl, optionallyfluorine-substituted cyclopropyl, bicyclo[1.1.1]pent-1-yl,1,1-dimethylpropargyl, 3-oxetanyl, methylamino, phenyl which isoptionally mono- or disubstituted by fluorine, amino or hydroxyl,thiadiazolyl,

R² represents hydroxyl, optionally ethoxycarbonyl-substituted alkoxyhaving 1 to 4 carbon atoms, benzyloxy, allyloxy, propargyloxy,

R³ represents hydrogen, amino, hydroxyl, methyl or fluorine,

A represents N or C—R⁷ in which

R⁷ represents hydrogen, halogen, CF₃, OCH₃, OCHF₂, CH₃, CN, CH═CH₂ orC≡CH or else together with R¹ may form a bridge of the structure—*O—CH₂—CH—CH₃ or —*O—CH₂—N—R⁸ where the atom marked with * is attachedto the carbon atom of A and in which

R⁸ is hydrogen or methyl,

B represents N, C—H, C—F, C—Cl, C—NH₂,

Y represents hydrogen or together with R² may form a bridge of thestructure —*S—NH— where the atom marked with * represents Y, and

T represents a radical of the formula

 in which

R⁴ represents H, CH₃, C₂H₅, optionally amino-substituted acyl having 1to 5 carbon atoms, alkoxycarbonyl, aminocarbonyl, alkylthiothiocarbonyland dialkoxyphosphoryl having 1 to 4 carbon atoms in the alkyl moiety,

R⁵ represents H, CH₃, C₂H₅ and

R⁶ represents H,

and their pharmaceutically useful hydrates and acid addition salts andto the alkali metal, alkaline earth metal, silver and guanidinium saltsof the parent carboxylic acids.

Particular preference is given to the compounds of the formula (I) inwhich

Q represents a radical of the formula

 in which

R¹ represents alkyl having 1 to 4 carbon atoms which is optionally mono-or disubstituted by fluorine, optionally fluorine-substitutedcyclopropyl, phenyl which is optionally mono- or disubstituted byfluorine,

R² represents hydroxyl, optionally ethoxycarbonyl-substituted alkoxyhaving 1 to 4 carbon atoms, benzyloxy, allyloxy, propargyloxy,

R³ represents hydrogen, amino, hydroxyl, methyl or fluorine,

A represents N or C—R⁷ in which

R⁷ represents hydrogen, chlorine, fluorine, OCH₃, OCHF₂, CH₃ or CN orelse together with R¹ may form a bridge of the structure —*O—CH₂—CH—CH₃,or —*O—CH₂—N—CH₃ where the atom marked with * is attached to the carbonatom of A,

B represents N, C—H, C—F,

Y represents hydrogen or together with R² may form a bridge of thestructure —*S—NH— where the atom marked with * represents Y, and

T represents a radical of the formula

 in which

R⁴ represents H, CH₃, C₂H₅, optionally amino-substituted acyl having 1to 4 carbon atoms or alkoxycarbonyl having 1 to 4 carbon atoms in thealkyl moiety,

R⁵ represents H and

R⁶ represents H,

and their pharmaceutically useful hydrates and acid addition salts andthe alkali metal, alkaline earth metal, silver and guanidinium salts ofthe parent carboxylic acids.

Most of the compounds which are suitable for the use according to theinvention have already been disclosed in European Patent Application 589318, or they can be prepared by the processes described therein. Thus,the compounds of the formula (I) are obtained, for example, by reactinga bicyclic amine T—H with a quinolone skeleton Q-Hal, where Halrepresents, for example, a halogen atom as leaving group, in accordancewith the equation below:

The 7-halogeno-quinolonecarboxylic acid derivatives Q-Hal used forpreparing the compounds of the formula (I) according to the inventionare known, or they can be prepared by known methods. Thus, the7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid or ethyl7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylatehave been described in European Patent Application 276 700. Thecorresponding 7-fluoro derivatives can also be synthesized, for example,via the reaction sequence below:

An alternative process for preparing the intermediate2,4-dichloro-3-cyano-5-fluorobenzoyl chloride (European PatentApplication 276 700), which can be converted into3-cyano-2,4,5-trifluoro-benzoyl fluoride, starts with5-fluoro-1,3-xylene: 5-fluoro-1,3-xylene is dichlorinated at the ring inthe presence of a catalyst under ionic conditions to give2,4-dichloro-5-fluoro-1,3-dimethylbenzene which is subsequentlychlorinated in the side chains under radical conditions to give2,4-dichloro-5-fluoro-3-dichloromethyl-1-trichloromethylbenzene. This ishydrolysed via the 2,4-dichloro-5-fluoro-3-dichloromethylbenzoic acid togive 2,4-dichloro-5-fluoro-3-formylbenzoic acid, which is subsequentlyconverted into 2,4-dichloro-5-fluoro-3-N-hydroxyiminomethyl-benzoicacid. Treatment with thionyl chloride gives2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride which can then beconverted into 3-cyano-2,4,5-trifluoro-benzoyl fluoride bychlorine-fluorine exchange.

The two five-membered rings in the bicyclic bases T—H employed arecis-linked. The bases T—H can be employed as racemates or asenantiomerically pure compounds. Various processes are suitable forpreparing the enantiomerically pure amines T—H:

1. The racemic bicyclic amines (T—H) can be reacted withenantiomerically pure acids, for example carboxylic acids or sulphonicacids, such as N-acetyl-L-glutamic acid, N-benzoyl-L-alanine,3-bromo-campher-9-sulphonic acid, campher-3-carboxylic acid,cis-campheric acid, campher-10-sulphonic acid, O,O′-dibenzoyl-tartaricacid, D- or L-tartaric acid, mandelic acid, methoxyphenylacetic acid,1-phenyl-ethanesulphonic acid, phenyl-succinic acid, to give a mixtureof the diastereomeric salts which can be separated into thediastereomerically pure salts by fractional crystallization. Theenantiomerically pure amines can be liberated by treating these saltswith alkali metal or alkaline earth metal hydroxides.

2. In a similar manner to that described under 1., an optical resolutionof the basic intermediates which are formed during the preparation ofthe racemic bicyclic amines can be carried out using the abovementionedenantiomerically pure acids.

3. Both the racemic amines (T—H) and some of the intermediates whichlead to the bicyclic amines (T—H) can, if appropriate after acylation,be separated chromatographically on chiral supports.

4. Using chemical linkage with chiral acyl radicals, it is also possibleto convert the racemic amines (T—H) into mixtures of diastereomers whichcan be separated by distillation, crystallization or chromatography intothe diastereomerically pure acyl derivatives from which theenantiomerically pure amines can be isolated by hydrolysis. Examples ofreagents for linkage with chiral acyl radicals include:methoxy-trifluoromethyl-phenylacetyl chloride, menthyl isocyanate, D- orL-phenylethyl isocyanate, menthyl chloroformate, campher-10-sulphonylchloride.

5. During the synthesis of the bicyclic amines (T—H), it is alsopossible to introduce chiral instead of achiral protective groups. Inthis way, mixtures of diastereomers which can be separated are obtained.In the intermediate7-benzyl-2-oxa-7-azabicyclo[3.3.0]octane-1-carbonitrile, for example,the benzyl radical can be replaced by a phenylethyl radical in the R orS configuration.

Examples of compounds according to the invention are, in addition to thecompounds mentioned in the preparation examples, the compounds listed inTable 1 below, which can be employed both in racemic form and asenantiomerically pure or diastereomerically pure compounds.

TABLE 1

A B R¹ R² R³ C—H C—F

OH H C—F C—F

OH H C—Cl C—F

OH H C—CH₃ C—F

OH H C—F C—CN

OH H C—F C—F

OH F N C—F

OH H C—F C—F

OH H C—F C—F

OC₂H₅ H C—CH₃ C—F

OH H C—CH₃ C—F

OH NH₂ C—F C—F

OH NH₂ N C—F

OH CH₃ C—H C—F 2,4-F₂C₆H₃ OH H

The compounds according to the invention have strong antibiotic activityand display a broad antibacterial spectrum against gram-positive andgram-negative pathogens, but in particular also against Helicobacterspp., while having low toxicity.

These useful properties make it possible to use them as chemotherapeuticactive compounds for the therapy of Helicobacter pylori infections andassociated gastroduodenal disorders which can be prevented, improvedand/or cured by the compounds according to the invention.

The compounds according to the invention can be administered in variouspharmaceutical preparations. Preferred pharmaceutical preparations aretablets, coated tablets, capsules, pills, granules, solutions,suspensions and emulsions.

Although the compounds according to the invention are administered asmonotherapeutic agents, they can also be used, if required, incombination with other therapeutics. Possible combination partnersinclude: nitroimidazole derivatives, for example metronidazole; protonpump inhibitors, for example omeprazole, pantoprazole or lanzoprazole;H₂-receptor antagonists, such as, for example, cimetidine, ranitidine,famotidine or nizatidine; bismuth compounds, such as, for example,bismuth salicylate or CBS (colloidal bismuth subcitrate); otherantibiotics, such as, for example, amoxicillin, azlocillin orclarithromycin; antacids.

The minimum inhibitory concentrations of some compounds according to theinvention are shown in an exemplary manner as a measure for theantibacterial activity in Table 2 below, in comparison to thestructurally similar7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylicacid (European Patent Application 671 391) and ciprofloxacin.

The minimum inhibitory concentrations (MIC) were determined in the agardilution test on Columbia agar or basis 2 agar (Oxoid) using 10% lysedhorse blood, either at pH 7 or pH 5, with 1 g of urea/l. The testsubstances were tested in replica dishes which contained concentrationsof the active compound which decreased in each case by a dilution factorof two. For inoculation, fresh Helicobacter cultures from liquid cultureor suspension of the pathogens from agar plates were used. Theinoculated agar plates were incubated at 37° C. in an atmospherecontaining 5-10% of CO₂ for 48-72 hours. The MIC value (μg/ml) which wasread off is the lowest concentration of active compound at which nogrowth was noticeable with the naked eye. The following Helicobacterisolates were used: H. felis ATCC 49179, H. pylori NCTC 11637, H. pyloriclinic isolate 008.

TABLE 2 MIC values (mg/l) of some compounds according to the inventionin comparison to a reference compound (Ref.*) (agar dilution test) MIC(mg/l) Example H. pylori 008 H. pylori 11637 1 B 0.06 0.25 1 BA 0.060.06 2 B 0.06 0.5 5 B 0.03 0.03 5 C 0.03 0.03 5 D 1 1 6 C 0.03 0.03 9 B<2 <2 10 B 0.06 0.06 11 B ≦0.015 0.03 12 B ≦0.015 0.03 12 C ≦0.015 0.0313 B ≦0.015 0.03 14 B ≦0.015 0.125 14 C ≦0.015 0.03 16 B 0.25 0.125 17 B0.125 0.25 18 B 0.125 0.125 23 B ≦0.015 ≦0.015 24 B 0.06 0.125 26 B 0.060.25 27 ≦0.015 0.5 29 8 8 30 0.25 0.125 31 <0.5 0.5 34 B 0.125 0.25Ciprofloxacin 0.125 0.125 Ref.*⁾ 0.25 0.25 *⁾Ref. =7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-5-vinyl-3-quinolinecarboxylicacid hydrochloride (European Patent Application 671 391)

As an example of the surprisingly high in vivo activity of the compoundsaccording to the invention, Table 3 shows the therapeutic success aftera 3-day treatment of infected mice with rac.7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride and for1S,5R-(+)-7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride (Example 5 C) in comparison to the treatment withCiprofloxacin: whereas the clearance rate with Ciprofloxacin is only17%, it is 67% and 100%, respectively, for the compounds according tothe invention. A 14-day treatment of the mice with 3×10 mg of rac.7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride/kg even resulted in a total eradication of thepathogen.

For studies in the animal model, female Swiss mice (8 to 12 weeks old,SPF breed) were kept with commercial feed and water. For colonization, adefined H. felis strain (ATCC 49179) was used. The bacteria wereadministered as a suspension (0.1 ml with 10⁸-10⁹ bacteria) 4 timeswithin 7 days using a pharyngeal tube. Alternatively, stomachhomogenates of mice which had been infected earlier were also used forinfection.

3-5 days after the infection had established itself, the treatment withthe test preparations was started. As a first treatment success, thereduction of the germs was determined as “clearance” 24 hours after thelast treatment (for example 3, 7, 10, 14 days; 1-3 times daily). In somecases, pathogen eradication 2-4 weeks after the end of the treatment wasalso determined. In accordance with the “CLO” test used in clinicaldiagnostics, a microtitre-based urease test was used. Defined stomachbiopsy specimens were tested for change of colour within a period of 24hours.

TABLE 3 Therapeutic success after a 3-day treatment of infected mice (6animals per group) Preparation Dose [mg/kg] Clearance % Substance A 2 ×10 4/6 67 Substance B 2 × 10 6/6 100 Ciprofloxacin 2 × 10 1/6 17

EXAMPLES

Preparation of the Intermediates

Example I1

At 25° C., 4.64 g (20 mmol) of1-aminomethyl-7-benzyl-2-oxa-7-aza-bicyclo[3.3.0]octane are dissolved in20 ml of water with 20 ml of 1N HCl. A solution of 1.98 g (22 mmol) ofpotassium cyanate in 20 ml of water is added and the mixture is heatedunder reflux for 1 hour. The mixture is concentrated at 60° C./15 mbar,the residue is eluted with dichloromethane and the eluate is dried withsodium sulphate and concentrated. This gives an oil (7.3 g) which ispurified chromatographically over silica gel usingdichloromethane/methanol/17% ammonia (150:20:1).

Yield: 4.0 g (72% of theory) of7-benzyl-1-ureidomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane as an oil,

¹H-NMR (400 MHz; CDCl₃): 4.9 broad (NH₂), 5.7 ppm broad (NH).

Example I2

In the presence of 2 g of Pd—C, 3.9 g (14 mmol) of7-benzyl-1-ureidomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane in 70 ml ofethanol are hydrogenated at 100° C./100 bar, the catalyst is filteredoff, the solution is concentrated and the resulting product (2.8 g of aviscous oil) is purified by chromatography.

Yield: 1.5 g (58% of theory) of1-ureidomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane as a viscous oil,

FAB-MS: m/e 186 [(M+H)⁺], 371 [(2M+H)⁺].

Example I3

7 g (30 mmol) of 1-aminomethyl-7-benzyl-2-oxa-7-aza-bicyclo[3.3.0]octaneare initially charged in 50 ml of dioxane and admixed with 3 g (30 mmol)of triethylamine, and 3 g (30 mmol) of acetic anhydride are addeddropwise with ice-cooling over a period of 10 minutes. The mixture isstirred at room temperature overnight and concentrated at 60° C./20mbar. The resulting residue is purified chromatographically over silicagel using dichloromethane/methanol/17% ammonia (150/20/1) as mobilephase.

Yield: 8.2 g of1-acetylaminomethyl-7-benzyl-2-oxa-7-aza-bicyclo[3.3.0]octane as an oil,content (according to GC): 94%.

Mass spectrum: 274 (M⁺), 202, 184, 170, 91 (100%).

Example I4

7.1 g (25.9 mmol) of1-acetylaminomethyl-7-benzyl-2-oxa-7-aza-bicyclo[3.3.0]octane aredissolved in 50 ml of tetrahydrofuran, and this solution is addeddropwise to a suspension of 3.1 g (82 mmol) of lithium aluminium hydridein 60 ml of tetrahydrofuran in such a way that the temperature is keptat from 31° to 33° C. The mixture is subsequently heated under refluxfor 12 hours and decomposed with cooling with 1.2 ml of water and 1.2 mlof 15% strength aqueous sodium hydroxide solution. The precipitate isfiltered off with suction and washed with tetrahydrofuran, and thefiltrate is concentrated. The oil that remains (5.5 g) is purifiedchromatographically over silica gel (mobile phase:dichloromethane/methanol/17% strength ammonia 150:20:1).

Yield: 4.55 g (67.5% of theory) of7-benzyl-1-ethylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane as an oil.

Example I5

1.4 g (5.4 mmol) of7-benzyl-1-ethylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane aredissolved in 6 ml of tert-butanol and admixed with a solution of 220 mg(5.5 mmol) of NaOH in 4 ml of water and 1.24 g (5.7 mmol) ofdi-tert-butyl dicarbonate. The temperature increases to 27°-31° C. Themixture is stirred overnight and concentrated and the residue is takenup in approximately 20 ml of water and extracted with dichloromethane.The extract is dried using sodium sulphate and concentrated underreduced pressure.

Yield: 1.58 g (81.5% of theory) of7-benzyl-1-(N-tert-butoxycarbonyl-N-ethylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octaneas an oil.

Example I6

In the presence of 0.8 g of Pd—C (10%), 3.5 g (9.7 mmol) of7-benzyl-1-(N-tert-butoxycarbonyl-N-ethylaminomethyl)-2-oxa-7-aza-bicyclo[3.3.0]octane in 60 ml ofethanol are hydrogenated at 70° C./90 bar. The catalyst is filtered offand washed with ethanol and the filtrate is concentrated. The residue ispurified chromatographically over silica gel (mobile phase:dichloromethane/methanol 95:5).

Yield: 2.0 g (76% of theory) of1-(N-tert-butoxycarbonyl-N-ethylaminomethyl)-2-oxa-7-aza-bicyclo[3.3.0]octaneas an oil.

Example I7

A:7-Benzyl-1-cyano-2-oxa-7-azabicyclo[3.3.0]octane(5-benzyl-hexahydrofuro[2,3-c]pyrrole-6a-carbonitrile)is prepared according to the procedure of European Patent Application589 318 and purified chromatographically (silica gel, dichloromethane).This racemic compound is separated into the enantiomers via achromatographic optical resolution (support: Daicel-Chiracell OJ), andthe enantiomers are reacted further via the subsequent steps, inaccordance with the procedures of European Patent Application 589 318.

B: 1.67 g (7.3 mmol) of(−)-7-benzyl-1-cyano-2-oxa-7-azabicyclo[3.3.0]octane in 23 ml ofabsolute tetrahydrofuran are reduced under reflux with 362 mg of lithiumaluminium hydride for 15 hours. The suspension is admixed with aqueouspotassium hydroxide solution, inorganic salts are filtered off withsuction and the filtrate is concentrated and purified by chromatography(silica gel, dichloromethane/methanol 2:1).

Yield: 1.30 g (76.6% of theory) of(−)-1-aminomethyl-7-benzyl-2-oxa-7-azabicyclo[3.3.0]octane as an oil,

[α]⁰: −6.9° (c=1.3, dichloromethane).

C: 1.2 g (5.2 mmol) of(−)-1-aminomethyl-7-benzyl-2-oxa-7-azabicyclo[3.3.0]octane in 6.5 ml oftert-butanol are admixed with 254 mg of NaOH in 5.1 ml of water, 1.3 gof di-tert-butyl pyrocarbonate are added and the mixture is stirred atroom temperature for approximately 30 minutes. The mixture is extractedwith dichloromethane and the extract is dried with potassium carbonateand concentrated. The resulting crude product is purifiedchromatographically (silica gel/dichloromethane 10:1).

Yield: 1.69 g (98% of theory) of(−)-(1S,5S)-1-tert-butoxycarbonylaminomethyl-7-benzyl-2-oxa-7-aza-bicyclo[3.3.0]octaneas an oil,

[α]⁰: −11.8° (c=1.16, dichloromethane).

D: 1.56 g (4.49 mmol) of(−)-(1S,5S)-1-tert-butoxycarbonylaminomethyl-7-benzyl-2-oxa-7-aza-bicyclo[3.3.0]octanein 50 ml of ethanol are hydrogenated at 100° C./90 bar in the presenceof 0.5 g of Pd—C (10%). The mixture is filtered, the filtrate isconcentrated and the residue is chromatographed over silica gel usingdichloromethane/methanol/17% ammonia (150:20:1) as mobile phase. Theconcentrated eluate crystallizes through.

Yield: 790 mg (73% of theory) of(−)-(1S,5S)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane,

Melting point: 104-105° C.,

[α]⁶: −10.2° (0.56, CHCi₃).

Example I8

5.6 g (16.8 mmol) of(+)-(1R,5R)-1-tert-butoxycarbonylaminomethyl-7-benzyl-2-oxa-7-aza-bicyclo[3.3.0]octane,[α]⁰: +13.1° (c=1.1, dichloromethane), which is prepared analogously tothe procedures in Examples I7 A to C, are hydrogenated in 100 ml ofethanol at 70° C./20 bar in the presence of 1 g of Pd—C (10%). Themixture is filtered, the filtrate is concentrated and the residue (3.5g) is chromatographed over silica gel using dichloromethane/methanol(95:5) as mobile phase. The concentrated eluate crystallizes through.

Yield: 2.54 g (63% of theory) of(+)-(1R,5R)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-azabicyclo[3.3.0]octane,

Melting point: 102-103° C.,

[α]⁶: +7.0° (0.3, CHCl₃).

Example I9A

A solution of 83 g (0.87 mol) of 2-cyano-4,5-dihydrofuran in 2000 ml ofabsolute ethyl acetate is initially charged at 15° C. At thistemperature, first 0.5 ml of trifluoroacetic acid and then 227 g (0.77mol, 85% strength) ofN-methoxymethyl-N-[(S)-1-phenylethyl]-N-trimethylsilylmethylamine areadded dropwise over a period of 10 minutes to this solution. During theaddition, the temperature increases to 45° C. The reaction mixture isstirred at room temperature overnight and subsequently washed with 200ml of saturated sodium bicarbonate solution. The organic phase is driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct is purified by silica gel column chromatography (toluene/ethylacetate, 99:1), giving a mixture of diastereomers (56 g, ratio of thediastereomers A:B=1.6:1). For crystallization, the residue is dissolvedin 100 ml of diethyl ether and slowly cooled to −35° C. The crystalswhich have precipitated out are filtered off through a cooled frit andwashed with a little diethyl ether which had been cooled to 60° C.

Yield: 13.3 g (7.1% of theory) of(1R,5R)-1-cyano-7-[(S)-1-phenylethyl]-2-oxa-7-azabicyclo[3.3.0]octane(diastereomer A),

Melting point: 68° C.,

[α]⁵: −34° (c=0.99, methanol). The absolute configuration was determinedby X-ray structure analysis.

Example I9B

The diastereomer B is obtained as the maleic acid salt by selectivecrystallization from the mixture which earlier gave the diastereomer A.To a solution of the mother liquor from Example I9A (103.3 g, 0.427 mol;ratio of diastereomers: 31:69, A:B) in 21 of ethyl acetate, for example,are added 49.5 g (0.427 mol) of maleic acid. The mixture is heated underreflux for 2 hours and cooled to room temperature overnight.

The crystals are subsequently filtered off with suction and shaken inethyl acetate and 1N aqueous sodium hydroxide solution and the organicphase is dried and concentrated. This gives the diastereomer B in apurity of >96% ee.

Yield: 32 g (45% of theory) of(1S,5S)-1-cyano-7-[(S)-1-phenylethyl]-2-oxa-7-azabicyclo[3.3.0]octane(diastereomer B).

The ethyl acetate solution which is enriched with the maleic acid saltof the diastereomer A is repeatedly extracted with water, and theaqueous phase is adjusted to pH 8 and extracted with ethyl acetate. Theorganic phase is subsequently dried and concentrated, giving a mixtureof isomers which is enriched with diastereomer A. This isomer mixturecan now be used to carry out the selective crystallization of thediastereomer A from ethyl acetate as described in Example I9A.

In this manner, the mixture of diastereomers can be separated completelyin several steps, so that the yield from Example I9A can be increased toapproximately 16% of theory or 26%, based on the proportion ofdiastereomer A.

Example 10A

At 30° C., a solution of 16.1 g (0.067 mol) of(1R,5R)-1-cyano-7-[(S)-1-phenylethyl]-2-oxa-7-azabicyclo[3.3.0]octane in70 ml of absolute tetrahydrofuran is added dropwise to 3.15 g (0.083mol) of lithium aluminium hydride in 70 ml of absolute tetrahydrofuran.The reaction mixture is then heated under reflux for 15 hours andsubsequently cooled to 10° C. and admixed successively with 3.5 ml ofwater, 3.5 ml of 15% strength potassium hydroxide solution and 3.5 ml ofwater. The precipitate is filtered off and washed with tetrahydrofuranand the filtrate is subsequently concentrated under reduced pressure.

Yield: 15.9 g of(1S,5R)-1-aminomethyl-7-[(S)-1-phenylethyl]-2-oxa-7-azabicyclo[3.3.0]octaneas crude product,

[α]⁵: −38.0° (c=1.21, methanol).

Example I10B

50 ml of liquid ammonia and 5 g of Raney nickel are added to a solutionof 15 g (0.062 mol) of(1R,5S)-1-cyano-7-[(S)-1-phenylethyl]-2-oxa-7-azabicyclo-[3.3.0]octanein 30 ml of tetrahydrofuran, and the mixture is then hydrogenated at 80°C. under a hydrogen pressure of from 110 to 120 bar for 5 hours. Afterthe reaction has gone to completion, the mixture is filtered throughCelite and concentrated.

Yield: 12.5 g (82% of theory) of(1R,5S)-1-aminomethyl-7-[(S)-1-phenylethyl]-2-oxa-7-azabicyclo[3.3.0]octane.

Example I11

At 10° C., 6.4 g (0.6 mol) of sodium carbonate and 13.0 g (0.6 mol) ofdi-tert-butyl dicarbonate are added successively to a solution of 13.4 g(0.545 mol) of(1S,5R)-1-aminomethyl-7-[(S)-1-phenylethyl]-2-oxa-7-azabicyclo[3.3.0]octanein 60 ml of dioxane. The mixture is stirred at room temperature for onehour and subsequently concentrated under reduced pressure. The residueis purified by silica gel column chromatography(dichloromethane/methanol, 95:5).

Yield: 18.9 g (quantitative) of(1S,5R)-1-tert-butoxycarbonylaminomethyl-7-[(S)-1-phenylethyl]-2-oxa-7-azabicyclo[3.3.0]octane,

[α]⁵: −19.0° (c=1.5 in methanol).

Example I12

18.0 g (0.052 mol) of(1S,5R)-1-tert-butoxycarbonylaminomethyl-7-[(S)-1-phenylethyl]-2-oxa-7-azabicyclo[3.3.0]octaneare dissolved in 150 ml of absolute methanol and, after addition of 2.5g of 10% palladium-activated carbon, hydrogenated at 70° C. and 20 barfor 9 h. The catalyst is filtered off and the filtrate is concentratedunder reduced pressure.

Yield: 12.5 g (99% of theory) of(1R,5R)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-azabicyclo[3.3.0]octane,

[α]⁶: +11.9° (c=0.7, methanol).

Treatment of(1R,5R)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-azabicyclo-[3.3.0]octanewith concentrated hydrochloric acid at room temperature gives(1S,5R)-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]octane hydrochloride.

Example I13

Ethyl8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate

A. Methyl 3-bromo-2,4,5-trifluoro-benzoate: with ice-cooling, 772 g of3-bromo-2,4,5-trifluoro-benzoyl fluoride are added dropwise to a mixtureof 1460 ml of methanol and 340 g of triethylamine. The mixture isstirred at room temperature for 1 hour. The reaction mixture isconcentrated, the residue is taken up in water and methylene chlorideand the aqueous phase is extracted with methylene chloride. The organicphase is dried over sodium sulphate and then concentrated, and theresidue is distilled under reduced pressure. This gives 752.4 g ofmethyl 3-bromo-2,4,5-trifluoro-benzoate of boiling point 122° C./20mbar.

B. Methyl 3-cyano-2,4,5-trifluoro-benzoate: 269 g of methyl3-bromo-2,4,5-trifluoro-benzoate and 108 g of copper cyanide in 400 mlof dimethylformamide are heated at reflux for 5 hours. All volatilecomponents of the reaction mixture are subsequently distilled off underreduced pressure. The distillate is then fractionated over a column.This gives 133 g of methyl 3-cyano-2,4,5-trifluoro-benzoate of boilingpoint 88-89° C./0.01 mbar.

C. 3-Cyano-2,4,5-trifluoro-benzoic acid: a solution of 156 g of methyl3-cyano-2,4,5-trifluoro-benzoate in 960 ml of glacial acetic acid, 140ml of water and 69 ml of concentrated sulphuric acid is heated at refluxfor 8 hours. Most of the acetic acid is subsequently distilled off underreduced pressure and the residue is admixed with water. The precipitatedsolid is filtered off with suction, washed with water and dried. Thisgives 118.6 g of 3-cyano-2,4,5-trifluoro-benzoic acid as a white solidof melting point 187-190° C.

D. 3-Cyano-2,4,5-trifluoro-benzoyl chloride: 111 g of3-cyano-2,4,5-trifluorobenzoic acid and 84 g of oxalyl chloride in 930ml of dry methylene chloride are, with addition of a few drops ofdimethylformamide, stirred at room temperature for 5 hours. Themethylene chloride is subsequently stripped off and the residue isdistilled under reduced pressure. This gives 117.6 g of3-cyano-2,4,5-trifluoro-benzoyl chloride as a yellow oil.

E. Ethyl 2-(3-cyano-2,4,5-trifluoro-benzoyl)-3-dimethylamino-acrylate: asolution of 55 g of 3-cyano-2,4,5-trifluoro-benzoyl chloride in 50 ml oftoluene is added dropwise to a solution of 36.5 g of ethyl3-dimethylamino-acrylate and 26.5 g of triethylamine in 140 ml oftoluene in such a way that the temperature remains between 50 and 55° C.The mixture is then stirred at 50° C. for another 2 hours. The reactionmixture is concentrated under reduced pressure and used for the nextstep without further work-up.

F. Ethyl2-(3-cyano-2,4,5-trifluoro-benzoyl)-3-cyclopropylamino-acrylate: at 20°C., 30 g of glacial acetic acid are added dropwise to the reactionproduct from step E. A solution of 15.75 g of cyclopropylamine in 30 mlof toluene is subsequently added dropwise. The mixture is stirred at 30°C. for 1 hour. 200 ml of water are then added, the mixture is stirredfor 15 minutes and the organic phase is separated off and once moreshaken with 100 ml of water. The organic phase is then dried over sodiumsulphate and concentrated under reduced pressure. The resulting crudeproduct is used for the next step without further work-up.

G. Ethyl8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate:the reaction product from step F and 27.6 g of potassium carbonate in 80ml of dimethylformamide are stirred at room temperature for 16 hours.The reaction mixture is then added to 750 ml of ice-water and the solidis filtered off with suction and washed with 80 ml of cold methanol.Drying gives 47 g of ethyl8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylateof melting point 209-211° C.

Example I14

2,4-Dichloro-5-fluoro-1,3-dimethylbenzene

a) Solvent-free

1 g of anhydrous iron(III) chloride is initially charged in 124 g of3,5-dimethylfluorobenzene and chlorine is introduced (approximately 4 h)at the rate of its consumption. The reaction is initially slightlyexothermic (temperature increase from 24 to 32° C.) and the temperatureis kept below 30° C. by cooling. After the introduction of 120 g ofchlorine, the mixture solidifies. According to GC analysis, 33.4% ofmonochloro compound, 58.4% of the desired product and 5% of more highlychorinated compounds have been formed. The hydrogen chloride is removedand the reaction mixture is subsequently distilled over a column underwater pump vacuum:

The initial fraction gives, at 72-74° C./22 mbar, 49 g of2-chloro-5-fluoro-1,3-dimethylbenzene. After an intermediate fraction of5 g, 75 g of 2,4-dichloro-5-fluoro-1,3-dimethylbenzene are distilledover at 105° C./22 mbar; melting range: 64-65° C.

b) In 1,2-dichloroethane

1 kg of 3,5-dimethyl-fluorobenzene and 15 g of anhydrous iron(III)chloride are initially charged in 1 l of 1,2-dichloroetane and chlorineis introduced at the rate of its consumption (approximately 4 h).Initially, the reaction is exothermic (temperature increase from 24 to32° C.), and the temperature is kept below 30° C. by cooling. After theintroduction of 1200 g of chlorine, GC analysis shows that 4% of themonochloro compound, 81.1% of the desired product and 13.3% of morehighly chlorinated compounds have been formed. Solvent and hydrogenchloride are distilled off and the residue is then distilled over acolumn under water pump vacuum:

The initial fraction gives 40 g of2-chloro-5-fluoro-1,3-dimethylbenzene. After a small intermediatefraction, 1115 g of 2,4-dichloro-5-fluoro-1,3-dimethylbenzene aredistilled over at 127-128° C./50 mbar.

Example I15

2,4-Dichloro-5-fluoro-3-dichloromethyl-1-trichloromethylbenzene

In a photochlorination apparatus fitted with a chlorine inlet and anoutlet for the hydrogen chloride to a washer and a light source in thevicinity of the chlorine inlet tube, 1890 g of2,4-dichloro-5-fluoro-1,3-dimethylbenzene are initially charged, andchlorine is metered in at from 140 to 150° C. Over a period of 30 h,3850 g of chlorine are introduced. According to GC analysis, the contentof desired product is 71.1%; the proportion of underchlorinatedcompounds is 27.7%.

Distillation over a 60 cm column with Wilson spirals gives an initialfraction of 1142 g which can be recycled into the chlorination. The mainfraction at 160-168° C./0.2 mbar gives 2200 g of2,4-dichloro-5-fluoro-3-dichloromethyl-1-trichloromethylbenzene of amelting range of 74-76° C. After recrystallization of a sample frommethanol, the melting point is 81-82° C.

Example I16

2,4-Dichloro-5-fluoro-3-formyl-benzoic Acid

In a stirred apparatus with gas outlet, 2500 ml of 95% strengthsulphuric acid are initially charged at 70° C., and 500 g of molten2,4-dichloro-5-fluoro-3-dichloromethyl-1-trichloromethylbenzene areadded dropwise with stirring. Evolution of hydrogen chloride startsafter a short while. Metered addition is continued for 2 h and themixture is stirred until the evolution of gas ceases. After cooling to20° C., the mixture is discharged under 4 kg of ice and the precipitatedsolid is filtered off with suction. The product is washed with water anddried.

Yield: 310 g,

Melting range: 172-174° C.

Example I17

2,4-Dichloro-5-fluoro-3-N-hydroxyiminomethyl-benzoic Acid

In a stirred apparatus, 80 g of hydroxylammonium chloride are initiallycharged in 500 ml of ethanol, 200 ml of 45% strength aqueous sodiumhydroxide solution are added dropwise and, at 40-45° C., 200 g of2,4-dichloro-5-fluoro-3-formyl-benzoic acid are subsequently introduced.The reaction is slightly exothermic, and stirring is continued at 60° C.for 5 h. After cooling to room temperature, the pH is adjusted to <3 bydropwise addition of hydrochloric acid, the product is taken up intert-butyl methyl ether, the organic phase is separated off and thesolvent is distilled off. 185 g of2,4-dichloro-5-fluoro-3-N-hydroxyiminomethyl-benzoic acid are obtainedas residue; melting range: 190-194° C.

Example I18

2,4-Dichloro-3-cyano-5-fluoro-benzoyl Chloride

In a stirred apparatus fitted with a metering device and a gas outletvia a reflux condenser to a washer, 600 ml of thionyl chloride areinitially charged and, at 20° C., 210 g of2,4-dichloro-5-fluoro-3-N-hydroxyiminomethyl-benzoic acid are introducedat the rate at which hydrogen chloride and sulphur dioxide are formed.After the addition, the mixture is heated under reflux until evolutionof gas has ceased. The mixture is subsequently distilled, giving, in aboiling range of 142-145° C./10 mbar, 149 g of2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride (content according to GC:98.1%); melting range: 73-75° C.

Example I19

3-Cyano-2,4,5-trifluoro-benzoyl Fluoride

50 g of potassium fluoride are suspended in 120 ml of tetramethylenesulphone and, at 15 mbar, subjected to incipient distillation(approximately 20 ml) for drying. 50.4 g of2,4-dichloro-3-cyano-5-fluoro-benzoyl chloride are subsequently addedand the mixture is stirred with exclusion of moisture at an internaltemperature of 180° C. for 12 hours. Vacuum distillation gives 32.9 g of3-cyano-2,4,5-trifluoro-benzoyl fluoride with a boiling range of 98-100°C./12 mbar.

Example I20

3-Cyano-2,4,5-trifluoro-benzoyl Chloride

76.6 g of 3-cyano-2,4,5-trifluoro-benzoyl fluoride, together with 1 g ofanhydrous aluminium chloride, are initially charged at 60-65° C., and 25g of silicon tetrachloride are then added dropwise at the rate at whichgas is given off. After the evolution of gas has ceased at 65° C., themixture is distilled under reduced pressure. In the boiling range of120-122° C./14 mbar, 73.2 g of 3-cyano-2,4,5-trifluoro-benzoyl chloridedistil over.

Example I21

0.5 g (2.07 mmol) of(1R,5R)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-azabicyclo[3.3.0]octanein 30 ml of ethanol are admixed with 13 ml of approximately 3.5 Nhydrochloric acid, and the mixture is stirred at room temperature for 4hours. The mixture is concentrated and the salt is isolated.

Yield: 0.3 g (67.5% of theory) of(1S,5R)-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]octane dihydrochloride,

Melting point: 284° C.,

[α]⁴: +16.5° (c=1, methanol).

(1R,5S)-1-Aminomethyl-2-oxa-7-azabicyclo[3.3.0]octane dihydrochlorideand (1SR,5RS)-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]octanedihydrochloride are also obtained correspondingly.

Preparation of the Active Compounds

Example 1

A: A mixture of 332 mg (1 mmol) of1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid in 4 ml of acetonitrile and 2 ml of dimethylformamide with 112 mg(1 mmol) of 1,4-diazabicyclo[2.2.2]octane and 267 mg (1.1 mmol) of1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane isheated under reflux for 1 hour. The suspension is concentrated at 70°C./15 mbar and the residue is admixed with a little water and treated inan ultrasonic bath for 30 minutes. The undissolved precipitate isfiltered off with suction, washed with water and dried at 90° C. underhigh vacuum.

Yield: 487 mg (88% of theory) of7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-8-difluoromethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

Melting point: 215-217° C. (decomposition).

B. 476 mg (0.86 mmol) of7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-8-difluoromethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are dissolved in 5 ml of hot, half-concentrated hydrochloric acid,and the solution is filtered and concentrated at 60° C./15 mbar. Theresidue is admixed with a little ethanol and reconcentrated, and thesalt is isolated and dried at 90° C. under high vacuum.

Yield: 385 mg (91% of theory) of7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-8-difluoromethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride,

Melting point: 182-185° C. (decomposition).

AA. By the method of step A,(+)-(1R,5R)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octaneis converted into(+)-(1R,5R)-7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-8-difluoromethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.

Melting point: 166-167° C. (decomposition),

[α]⁵: +26° (c=0.25, DMF).

BA. By the method of step B, the product from step AA is converted into(−)-(1S,5R)-7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-fluoromethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride.

Melting point: 194-197° C. (decomposition),

[α]⁵: −21° (c=0.5, DMF).

AB. By the method of step A,(−)-(1S,5S)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octaneis converted into(−)-(1S,5S)-7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-8-difluoromethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.

Melting point: 166-167° C. (decomposition),

[α]⁵: −27° (c=0.125, DMF).

BB. By the method of step B, the product from step AB is converted into(+)-(1R,5S)-7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-8-difluoromethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride.

Melting point: 194-197° C. (decomposition),

[α]⁵: +19° (c=0.5, DMF).

Example 2

A: By the method of Example 1A,5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid are converted into5-amino-7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid (77% of theory) of melting point 219-221° C. (decomposition) (afterchromatographic purification over silica gel usingdichloromethane/methanol/17% aqueous ammonia 150/20/1 as mobile phase).

B: By method of Example 1B, 405 mg (0.76 mmol) of the product from stepA are reacted with 7 ml of half-concentrated hydrochloric acid.

Yield: 244 mg (69% of theory) of5-amino-7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid hydrochloride,

Melting point: 242-244° C. (decomposition).

FAB-MS: m/e 433 [(M+H)⁺].

C: 235 mg (0.44 mmol) of the product from step A are dissolved at roomtemperature in 20 ml of dichloromethane and admixed with 1.4 ml oftrifluoroacetic acid. The mixture is stirred at room temperature for 3hours and then concentrated, and the residue is evaporated twice withethanol. This gives 148 mg of5-amino-7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid trifluoroacetate as crude product which is purified over 40 g ofsilica gel using dichloromethane/methanol/17% aqueous ammonia (150/20/1)as mobile phase, giving the betain.

Yield: 69 mg (36% of theory) of5-amino-7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid,

Melting point: 209-211° C. (decomposition).

Example 3

A: By the method of Example 1A,1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid are converted into7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid (76% of theory).

B: By the method of Example 1B, the product from step A is reacted withhalf-concentrated hydrochloric acid to give7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylicacid hydrochloride of melting point 251-253° C. (decomposition).

Example 4

A: By the method of Example 1A,6,7,8-trifluoro-1,4-dihydro-1-methylamino4-oxo-3-quinolinecarboxylicacid are converted into7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid (68% of theory) of melting point 225-227° C. (decomposition).

B: By the method of Example 1B, the product from step A is reacted withhalf-concentrated hydrochloric acid to give, in a yield of 65%,7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-6,8-difluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylicacid hydrochloride of melting point 177-179° C. (decomposition). FAB-MS:m/e: 395 [(M+H)⁺], 366.

Example 5

A. R=(CH₃)₃C—O—CO

B. R=H×HCl

A: By the method of Example 1A,7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (European Patent 276 700) is converted into7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.

B: By the method of Example 1B, the product from step A is reacted withhalf-concentrated hydrochloric acid to give7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride of melting point 241° C. (decomposition).

C. By the method of the reactions in steps A and B,(+)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octanegives(+)-7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride,

Melting point: 293° C. (decomposition),

[α]⁴: +50.6° (c=0.7, methanol).

D. By the method of the reactions in steps A and B,(−)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octanegives(−)-7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride,

Melting point: 292° C. (decomposition),

[α]⁴: −49° (c=1, methanol).

E: A solution of 5.4 g (0.224 mmol) of(1R,5R)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-azabicyclo[3.3.0]octane,6.5 g (0.204 mol) of ethyl8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylateand 4.6 g (0.459 mol) of triethylamine and 300 ml of absoluteacetonitrile is stirred at room temperature overnight. The mixture issubsequently concentrated under reduced pressure and the residue ischromatographed over silica gel (dichloromethane/methanol, 99:1→95:5).This gives 9.2 g (83.6% of theory) of ethyl(+)-7-[(1R,5R)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl]-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylate,

[α]⁴: +81.1° (c=1.5, dichloromethane).

9.1 g (0.169 mol) of ethyl(+)-7-[(1R,5R)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl]-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylateare admixed with 150 ml of 10% strength hydrochloric acid. The mixtureis heated under reflux for 1 hour and subsequently cooled to roomtemperature. The colourless crystals are filtered off and washed with alittle absolute isopropanol.

Yield: 6.9 g (91% of theory) of(+)-7-[(1S,5R)-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]oct-7-yl]-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylicacid hydrochloride,

Melting point: 293° C.,

[α]⁴: +50.60° (c=0.8 in methanol).

Example 6

A: 172 mg (0.5 mmol) of1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid-BF₂-chelate in 5 ml of acetonitrile/dimethylformamide (1:1) areadmixed with 150 mg (0.62 mmol) of1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicylco[3.3.0]octane and 40mg (0.38 mmol) of 1,4-diazabicyclo[2.2.2]octane and heated at 40° C. for12 hours. The mixture is concentrated and can be used as crude productin step B. However, it can also be purified chromatographically oversilica gel (mobile phase: dichloromethane/methanol 95:5) to characterizethe intermediate step. This gives 128 mg of7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid-BF₂-chelate as a yellow solid; FAB-MS: m/e 566 [(M+H)⁺], 546[(M−F⁻)⁺].

B: The evaporation residue obtained from step A is taken up in 20 ml ofdichloromethane/methanol (1:1) and, after addition of 2.6 ml oftriethylamine, heated under reflux for 10 hours. The mixture isconcentrated and the residue is taken up in 4 ml of water and admixedwith 3 ml of 2N HCl. The precipitate is filtered off with suction,washed with 20 ml of water and dried at 80° C. under high vacuum. Thisgives 210 mg of7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylicacid;

¹H-NMR (400 MHz; DMSO): δ3.63 ppm s (OCH₃).

C: 206 mg (0.4 mmol) of the product from step B are dissolved in 13 mlof dichloromethane and admixed with 3.4 ml of trifluoroacetic acid. Thesolution is stirred at 25° C. for 30 minutes and then concentrated underreduced pressure. The residue is stirred repeatedly with absoluteethanol and the precipitate is filtered off with suction, washed wellwith ethanol and dried at 80° C. under high vacuum.

Yield: 114 mg (54% of theory) of7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylicacid trifluoroacetate,

Melting point: 215-216° C. (decomposition).

Example 7

A: 313 mg (1 mmol) of7,8-dichloro-1-cyclopropyl-1,4-dihydro-5-methyl-4-oxo-1,6-naphthyridine-3-carboxylicacid in 5 ml of acetonitrile are admixed with 168 mg (1.5 mmol) of1,4-diazabicyclo[2.2.2]octane and 266 mg (1.1 mmol) of1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane andstirred at 50° C. for 2 hours. The mixture is concentrated, the residueis treated with water, and the precipitate is filtered off with suction,washed with water and dried at 90° C. under high vacuum.

Yield: 272 mg (52.5% of theory) of7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-8-chloro-1-cyclopropyl-1,4-dihydro-5-methyl-4-oxo-1,6-naphthyridine-3-carboxylicacid,

Melting point: 209-210° C. (decomposition).

B: 150 mg (0.29 mmol) of the product from step A in 2 ml ofdichloromethane are admixed with 1.5 ml of trifluoroacetic acid andstirred at 25° C. for 45 minutes. The solution is concentrated and theresidue is repeatedly admixed with dichloromethane and reconcentrated.The resulting salt is isolated and dried at 70° C. under high vacuum.

Yield: 68 mg (45% of theory) of7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-8-chloro-1-cyclopropyl-1,4-dihydro-5-methyl-4-oxo-1,6-naphthyridine-3-carboxylicacid trifluoroacetate,

Melting point: 125-128° C. (decomposition).

Mass spectrum (ESI): m/e 419 [(M+H)⁺].

Example 8

A: By the method of Example 7A, ethyl7-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylateare converted, in a yield of 20%, into ethyl7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylateof melting point 146-148° C. (decomposition).

B: By the method of Example 7B, the product from step A is reacted withtrifluoroacetic acid to give ethyl7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylatetrifluoroacetate of melting point 199-200° C. (decomposition).

C: 136 mg (0.25 mmol) of the product from step B are admixed with 10 mlof half-concentrated hydrochloric acid and heated under reflux forapproximately 30 minutes. The mixture is concentrated and the residue istreated with ethanol. The solid is filtered off with suction and driedat 80° C. under high vacuum.

Yield: 97 mg (91% of theory) of7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylicacid hydrochloride,

Melting point: 301-304° C. (decomposition).

Example 9

A: By the method of Example 1A, ethyl1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylateis converted into ethyl7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate.

B: 1.2 g of the product from step A in 10 ml of trifluoroacetic acid arestirred at 25° C. for 5 minutes and then concentrated, and the residueis stirred with ether. The resulting solid is purifiedchromatographically in dichloromethane/methanol (95:5) over a littlesilica gel.

Yield: 215 mg (17% of theory) of ethyl7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylatetrifluoroacetate,

Melting point: 139-141° C.

Example 10

A: 4.96 g (10 mmol) of7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are suspended in 200 ml of tetrahydrofuran/water (1:1) at 25° C.,admixed with 2.3 g (7 mmol) of caesium carbonate and treated in anultrasonic bath for approximately 10 minutes, resulting in a clearsolution. At 30° C./15 mbar, most of the mixture is evaporated and theremaining solution is lyophilized. This gives 7.4 g of a colourlessresidue which mainly comprises the caesium salt of7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid which is contaminated by some inorganic salt. 637 mg of thiscaesium salt are dissolved in 5 ml of dimethylformamide at 25° C. andadmixed with 213 mg (1.5 mmol) of methyl iodide. The suspension isstirred at 25° C. overnight and then concentrated on a rotary evaporatorand the residue is treated with light naphtha and dried at 80° C. underhigh vacuum.

Yield: 360 mg of methyl7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate,

Melting point: 141-144° C. (decomposition).

B: The product obtained from step A is dissolved in 25 ml ofdichloromethane, admixed with 1.5 ml of trifluoroacetic acid and stirredat room temperature for 2 hours. The solution is concentrated underreduced pressure and the residue is purified chromatographically oversilica gel using dichloromethane/methanol/17% ammonia=150:20:1. Theresulting product is initially charged in 2 ml of water and dissolvedwith 0.76 ml of 1N HCl. The mixture is concentrated at 60° C./15 mbarand the salt is dried at 50° C. under high vacuum.

Yield: 226 mg of methyl7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylatehydrochloride,

Melting point: 109-111° C.

Example 11

A: By the method of Example 10A, 1-bromobutane gives 1-butyl7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylateof melting point 146-148° C.

B: By the method of Example 10B, the protecting group is cleaved offwith trifluoroacetic acid and the resulting trifluoroacetate is purifiedchromatographically using the ammoniacal mobile phase. 1-Butyl7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylateof melting point 117-119° C. (decomposition) is isolated.

Example 12

A: By the method of Example 10A, allyl bromide gives allyl7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylateof melting point 143-145° C.

B: By the method of Example 10B, the protecting group is cleaved offwith trifluoroacetic acid and the resulting trifluoroacetate is purifiedchromatographically using the ammoniacal mobile phase. Allyl7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylateof melting point 133-135° C. (decomposition) is isolated.

C: By the method of Example 10B, the protecting group is cleaved offwith trifluoroacetic acid and the resulting crude trifluoroacetate istreated with ethanol and ether and isolated as a solid: allyl7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylatetrifluoroacetate of melting point 118-119° C. (decomposition).

Example 13

A: By the method of Example 10A, propargyl bromide gives propargyl7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylateof melting point 159-160° C.

B: By the method of Example 10B, the protecting group is cleaved offwith trifluoroacetic acid and the resulting trifluoroacetate is purifiedchromatographically using the ammoniacal mobile phase. Propargyl7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylateof melting point 127-129° C. (decomposition) is isolated.

Example 14

A: By the method of Example 10A, benzyl bromide gives benzyl7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylateof melting point 148-149° C.

B: By the method of Example 10B, the protecting group is cleaved offwith trifluoroacetic acid and the resulting trifluoroacetate is purifiedchromatographically using the ammoniacal mobile phase. Benzyl7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylateof melting point 118-119° C. (decomposition) is isolated.

C: By the method of Example 10B, the protecting group is cleaved offwith trifluoroacetic acid and the resulting crude trifluoroacetate istreated with ethanol and ether and isolated as a solid: benzyl7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylatetrifluoroacetate of melting point 119-120° C. (decomposition).

Example 15

A: By the method of Example 10A, ethyl bromoacetate givesethoxycarbonylmethyl7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylateof melting point 150-152° C.

B: By the method of Example 10B, the protecting group is cleaved offwith trifluoroacetic acid and the resulting trifluoroacetate is purifiedchromatographically using the ammoniacal mobile phase.Ethoxycarbonylmethyl7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylateof melting point 144-146° C. (decomposition) is isolated.

Example 16

A: By the method of Example 1A,1-(cis-2-fluoro-cyclopropyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid is converted into7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-(cis-2-fluorocyclopropyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (74% of theory) of melting point 202-206° C. (decomposition).

B: By the method of Example 1B, the product from step A is reacted withhalf-concentrated hydrochloric acid to give7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-(cis-2-fluoro-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride of melting point 257-259° C. (decomposition).

Example 17

A: By the method of Example 1A,1-tert-butyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acidis converted into7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-tert-butyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (84% of theory) of melting point 131-133° C. (decomposition).

B: By the method of Example 1B, the product from step A is deblockedwith half-concentrated hydrochloric acid for 15 minutes and theresulting crude product is purified chromatographically over silica gelusing an ammoniacal mobile phase (dichloromethane/methanol/17% ammonia30:8:1). In addition to7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (melting point: >330° C.), this gives7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-tert-butyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid of melting point 217-218° C. (decomposition).

Example 18

A: By the method of Example 1A,1-(fluoro-tert-butyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid is converted into7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-(fluoro-tert-butyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (81% of theory) of melting point 161-162° C. (decomposition).

B: By the method of Example 1B, the product from step A is deblockedwith trifluoroacetic acid and the crude product which is obtained afterconcentration is crystallized by treatment with ethanol. This gives7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-(fluoro-tert-butyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid trifluoroacetate of melting point 197-198° C. (decomposition).

Example 19

A: By the method of Example 1A,1-(difluoro-tert-butyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid is converted into7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-(difluoro-tert-butyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (59% of theory).

B: By the method of Example 6C, the product from step A is deblockedwith trifluoroacetic acid in dichloromethane, the crude product which isobtained after concentration is taken up in water and washed withdichloromethane and the aqueous phase is lyophilized. This gives, in ayield of 12%,7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-(difluoro-tert-butyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid trifluoroacetate of melting point 154-160° C. (decomposition).

Example 20

A: By the method of Example 1A,1-(trifluoro-tert-butyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid is converted into7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-(trifluoro-tert-butyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (73% of theory) of melting point 131° C.

B: By the method of Example 1B, the product from step A is deblockedwith hydrochloric acid. This gives, in a yield of 41%,7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-(trifluoro-tert-butyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride of melting point 228° C. (decomposition).

Example 21

A: By the method of Example 1A,1-cyclopropyl-6,7-difluoro-5-hydroxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid is converted into7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6-fluoro-5-hydroxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid (63% of theory).

B: By the method of Example 1B, the product from step A is reacted withhalf-concentrated hydrochloric acid to give7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6-fluoro-5-hydroxy-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride of melting point 225° C. (decomposition).

Example 22

A: By the method of Example 1A,7-chloro-6-fluoro-1,4-dihydro-4-oxo-1-(1,2,5-thiadiazol-3-yl)-1,8-naphthyridine-3-carboxylicacid is converted into7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-6-fluoro-1,4-dihydro-4-oxo-1-(1,2,5-thiadiazol-3-yl)-1,8-naphthyridine-3-carboxylicacid (66% of theory).

B: By the method of Example 1B, the product from step A is reacted withhalf-concentrated hydrochloric acid to give7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-6-fluoro-1,4-dihydro-4-oxo-1-(1,2,5-thiadiazol-3-yl)-1,8-naphthyridine-3-carboxylic acid hydrochlorideof melting point 207° C. (decomposition).

Example 23

A: A mixture of 481 mg (1.7 mmol) of1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid in 5 ml of acetonitrile and 2.5 ml of dimethylformamide with 217 mg(1.9 mmol) of 1,4-diazabicyclo[2.2.2]octane and 467 mg (1.9 mmol) of(+)-(1R,5R)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octaneis heated under reflux for 5 hours, and the solution is filtered hot.The reaction product crystallizes out and is filtered off with suctionand washed with a little acetonitrile. The precipitate is subsequentlystirred well with approximately 40 ml of water, filtered off withsuction and dried at 80° C. under high vacuum.

Yield: 748 mg (87% of theory) of(+)-(1R,5R)-7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

Melting point: 202-203° C. (decomposition).

[α]³: +94° (c=0.46, CHCl₃).

B: 701 mg (1.39 mmol) of(+)-(1R,5R)-7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are dissolved in 16 ml of hot, half-concentrated hydrochloric acidand the solution is filtered and concentrated at 60° C./15 mbar. Theresidue is admixed with some ethanol and reconcentrated, and the salt isisolated and dried at 80° C. under high vacuum.

Yield: 537 mg (88% of theory) of(+)-(1S,5R)-7-(aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride,

Melting point: 214-216° C. (decomposition).

[α]³: +49° (c=0.45, DMF).

ee>99.8% (determined by capillary electrophoresis).

Example 24

A: By the method of Example 23 A,(−)-(1S,5S)-1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octanegives, in a yield of 67%,(−)-(1S,5S)-7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylicacid,

Melting point: 209-210° C. (decomposition).

[α]³: −96° (c=0.43, CHCl₃).

B: By the method of Example 23 B, the product from step A is deblockedby reaction with hydrochloric acid to give(−)-(1RS,5S)-7-(aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride,

Melting point: 214-216° C. (decomposition).

[α]³: −49° (c=0.33, DMF).

ee>99.8% (determined by capillary electrophoresis).

Example 25

A: 250 mg (0.85 mmol) of9-cyclopropyl-6,7-difluoro-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dionein 10 ml of absolute pyridine and 247 mg (1.02 mmol) of1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane areheated under reflux overnight. After cooling, the mixture is admixedwith 40 ml of water and the precipitate is filtered off with suction,washed with water and dried under reduced pressure. This gives 190mg of7-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-9-cyclopropyl-6-fluoro-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dione.

B: The product from step A is, by the method of Example 6C, deblockedwith trifluoroacetic acid in dichloromethane, the solution isconcentrated and evaporated repeatedly with a little toluene, theresidue is taken up in 5 ml of methanol and the salt is precipitated outusing 20 ml of isopropanol.

Yield: 163 mg of7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-9-cyclopropyl-6-fluoro-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinoline-3,4-dionetrifluoroacetate,

Melting point: 215° C. (decomposition).

Example 26

A: 0.72 g (2.72 mmol) of9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,3,4]-benzoxadiazine-6-carboxylicacid in 36 ml of acetonitrile is admixed with 0.4 g (2.8 mmol) of1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane and0.6 g of 1,4-diazabicyclo[2.2.2]octane and the mixture is heated underreflux for 16 hours. The mixture is concentrated and the residue istaken up in water and extracted with dichloromethane. The extract isthen dried with sodium sulphate and concentrated, the residue is stirredwith methanol and the resulting solid is isolated and dried underreduced pressure. This gives 0.6 g of10-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,3,4]-benzoxadiazine-6-carboxylicacid of melting point 176° C.

B: 0.6 g (1.9 mmol) of the product from step A is dissolved in 105 ml of4N hydrochloric acid/dioxane (1:1) and heated at 60° C. for 2 hours. Thesolution is concentrated and stirred with some ethanol and theprecipitate is filtered off with suction and dried.

Yield: 110 mg of10-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,3,4]-benzoxadiazine-6-carboxylicacid hydrochloride,

Melting point: 233° C.

Example 27

A mixture of 283 mg (1 mmol) of1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro4-oxo-3-quinolinecarboxylicacid in 4 ml of acetonitrile and 2 ml of dimethylformamide and 112 mg (1mmol) of 1,4-diazabicyclo[2.2.2]octane and 234 mg (1.3 mmol) of1-ureidomethyl-2-oxa-7-aza-bicyclo[3.3.0]octane is heated under refluxfor 2 hours. The mixture is concentrated and the residue is admixed withsome water and treated in an ultrasonic bath. The undissolvedprecipitate is filtered off with suction, washed with water and dried at100° C. under high vacuum.

Yield: 237 mg (53% of theory) of1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-ureidomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-3-quinolinecarboxylicacid,

Melting point: 185-187° C. (decomposition).

Example 28

By the method of Example 27,8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-ureidomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-3-quinolinecarboxylicacid is obtained,

Melting point: 232-234° C. (decomposition).

Example 29

By the method of Example 27,1-cyclopropyl-8-difluoromethoxy-6-fluoro-1,4-dihydro-4-oxo-7-(1-ureidomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-3-quinolinecarboxylicacid is obtained,

Melting point: 232-234° C. (decomposition).

Example 30

By the method of Example 27,8-chloro-6-fluoro-1-[(1R,2S)-2-fluoro-cyclopropyl]-1,4-dihydro-4-oxo-7-(1-ureidomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-3-quinolinecarboxylicacid is obtained,

Melting point: 208-210° C. (decomposition).

Example 31

310 mg (1 mmol) of7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid in 2.3 ml of dimethylformamide is heated under reflux with 2.3 mlof formic acid for 8 hours. The mixture is concentrated under reducedpressure, the residue is stirred with 8 ml of water and the precipitateis filtered off with suction, dried and chromatographed over silica gelusing dichloromethane/methanol (95:5) as mobile phase.

Yield: 173 mg (40% of theory) of1-cyclopropyl-6,8-difluoro-7-(1-formylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1,4-dihydro4-oxo-3-quinolinecarboxylicacid,

Melting point: 208-209° C. (decomposition),

Example 32

730 mg (2 mmol) of7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are initially charged at room temperature in a mixture of 1.3 ml ofwater and 1 ml of 4N aqueous sodium hydroxide solution, and the mixtureis cooled with ice and admixed with 0.24 ml of carbon disulphide. Themixture is stirred at 5° C. for 1 hour and subsequently at roomtemperature for another 15 hours. The suspension is admixed with 50 mlof acetone and cooled, and the precipitate is filtered off with suction,washed with acetone and dried at 80° C. under high vacuum. This gives657 mg of the sodium salt of the dithiourethane. 409 mg of this sodiumsalt are initially charged in 5 ml of dimethylformamide and admixed with123 mg of 1-bromopropane in 1 ml of dimethylformamide, and the mixtureis stirred at room temperature overnight. The mixture is concentrated at70° C./12 mbar, the residue is stirred with ethanol, the precipitate isfiltered off with suction and dried and the resulting crude product (225mg) is purified by chromatography over silica gel usingdichloromethane/methanol/17% ammonia (150:4:1).

Yield: 56 mg of7-(1-propylthio-thiocarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

Melting point: 162-166° C. (decomposition).

Example 33

395 mg (1 mmol) of7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid in 15 ml of dichloromethane are admixed with 406 mg (2 mmol) ofbis(trimethylsilyl)acetamide and stirred at 25° C. for 3 hours. Themixture is subsequently admixed with 173 mg (1 mol) of diethylphosphorylchloride and stirred at room temperature for 24 hours. Unreactedstarting material is filtered off with suction, the mother liquor isconcentrated and the residue is chromatographed over silica gel (mobilephase: dichloromethane/methanol 95:5).

Yield: 73 mg (1.5%) of7-(1-diethoxyphosphoryl-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

FAB-MS: m/e 542 [(M+H)⁺], 524.

Example 34

A: A mixture of 283 mg (1 mmol) of1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid in 3 ml of acetonitrile and 1.5 ml of dimethylformamide and 120 mg(1.07 mmol) of 1,4-diazabicyclo[2.2.2]octane and 400 mg of (1.5 mmol) of1-(N-tert-butoxycarbonyl-N-ethyl-aminomethyl)-2-oxa-7-aza-bicyclo[3.3.0]octaneis heated under reflux for 6 hours, the solution is concentrated, andthe residue is admixed with 20 ml of water and treated in an ultrasonicbath. The undissolved precipitate is filtered off with suction, washedwith water and dried at 80° C. under high vacuum.

Yield: 460 mg (86% of theory) of7-[1-(N-tert-butoxycarbonyl-N-ethylaminomethyl)-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid,

Melting point: 166-168° C. (decomposition).

B: 430 mg (0.8 mmol) of the product from step A are dissolved in 15 mlof hot, half-concentrated hydrochloric acid, and the solution isfiltered and concentrated at 60° C./15 mbar. The residue is admixed withsome ethanol and reconcentrated, and the salt is isolated and dried at80° C. under high vacuum.

Yield: 272 mg (72% of theory) of7-(ethylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid hydrochloride,

Melting point: 280-281° C. (decomposition).

Example 35

A: By the method of Example 1A,9,10-difluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylicacid is converted into10-(1-tert-butoxycarbonylaminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-9-fluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylicacid of melting point 157-158° C. (decomposition).

B: By the method of Example 1B, the product from step A is reacted withhalf-concentrated hydrochloric acid to give10-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-9-fluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyridol[1,2,3-de][1,4]benzoxazine-6-carboxylicacid hydrochloride of melting point 191-193° C. (decomposition).

Example 36

350 mg (1.21 mmol) of ethyl8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro4-oxo-quinolinecarboxylateand 260 mg (1.2 mmol) of(1SR,5RS)-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]octane dihydrochloridein 30 ml of absolute acetonitrile are admixed with 470 mg (4.64 mmol) oftriethylamine and stirred at room temperature overnight. The mixture isconcentrated and the residue is purified chromatographically (silicagel; dichloromethane/methanol 9:1). 450 mg (86% of theory) of ethyl7-([1SR,5RS]-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]oct-7-yl)-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylateare isolated, melting point: 193° C.

Ethyl7-([1R,5S]-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]oct-7-yl)-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylateand7-([1S,5R]-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]oct-7-yl)-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylateare also prepared in a corresponding manner.

What is claimed is:
 1. A diastereomerically pure or enantiomericallypure compound from the group consisting of7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-1-cyclopropyl-8-difluoromethoxy-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid, and7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid.
 2. The compound(+)-7-[(1S,5R)-1-Aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl]-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylicacid.
 3. A pharmaceutical composition comprising the compound accordingto claim 2 and a pharmaceutical acceptable carrier.
 4. A method oftreating a Heliobacter pylori infection or a gastroduodenal disorderassociated therewith, said method comprising administering to a patientin need thereof an effective amount therefor of at least one compound ofthe formula (I): T—Q  (I), in which Q represents a radical of theformulae

 in which R¹ represents alkyl having 1 to 4 carbon atoms which isoptionally mono- to trisubstituted by halogen or hydroxyl, alkenylhaving 2 to 4 carbon atoms, cycloalkyl having 3 to 6 carbon atoms whichis optionally substituted by 1 or 2 fluorine atoms,bicyclo[1.1.1]pent-1-yl, 1,1-dimethylpropargyl, 3-oxetanyl, methoxy,amino, methylamino, dimethylamino, phenyl which is optionally mono- ordisubstituted by halogen, amino or hydroxyl, isoxazolyl, orthiadiazolyl; R² represents hydroxyl, alkoxy having 1 to 4 carbon atomswhich is optionally substituted by hydroxyl, methoxy, amino,dimethylamino or ethoxycarbonyl, benzyloxy, allyloxy, propargyloxy or(5-methyl-2-oxo-1,3-dioxol-4-yl)-methyloxy, acetoxymethyloxy,pivaloyloxymethyloxy, 5-indanyloxy, phthalidinyloxy,3-acetoxy-2-oxo-butyloxy, nitromethyl or dialkoxycarbonylmethyl having 1to 2 carbon atoms in each alkyl moiety; R³ represents hydrogen, amino,hydroxyl, or halogen; A represents N or C—R⁷ in which R⁷ representshydrogen, halogen, CF₃, OCH₃, OCHF₂, CH₃, CN, CH═CH₂ or C≡CH or elsetogether with R¹ may form a bridge of the structure —*O—CH₂—CH—CH₃,—*S—CH₂—CH₂—, —*S—CH₂—CH—CH₃, —*CH₂—CH₂—CH—CH₃ or —*O—CH₂—N—R⁸ where theatom marked with * is attached to the carbon atom of A and in which R⁸represents hydrogen, methyl or formyl; B represents N, C—H, C—F, C—Cl,C—NO₂, C—NH₂; Y represents hydrogen or together with R² may form abridge of the structure —*S—NH— where the atom marked with * representsY; and T represents a radical of the formula:

 in which R⁴ represents H, CH₃, C₂H₅, optionally amino-substituted acylhaving 1 to 5 carbon atoms, alkoxycarbonyl, aminocarbonyl,alkylthio-thiocarbonyl and dialkoxyphosphoryl having 1 to 4 carbon atomsin the alkyl moiety; R⁵ represents H, CH₃ or C₂H₅; and R⁶ represents Hor CH₃; or a pharmaceutically useful hydrate, acid addition salt oralkali metal, alkaline earth metal, silver or guanidinium salt thereof.5. The method according to claim 4, wherein in the compound of formula(I): R¹ represents alkyl having 1 to 4 carbon atoms which is optionallymono- to trisubstituted by fluorine, represents vinyl, optionallyfluorine-substituted cyclopropyl, bicyclo[1.1.1]pent-1-yl,1.1-dimethylpropargyl, 3-oxetanyl, methylamino, phenyl which isoptionally mono- or disubstituted by fluorine, amino or hydroxyl, orrepresents thiadiazolyl; R² represents hydroxyl, optionallyethoxycarbonyl-substituted alkoxy having 1 to 4 carbon atoms, benzyloxy,allyloxy, or propargyloxy; R³ represents hydrogen, amino, hydroxyl, orfluorine; A represents N or C—R⁷ in which R⁷ represents hydrogen,halogen, CF₃, OCH₃, OCHF₂, CH₃, CN, CH═CH₂ or C≡CH or else together withR¹ may form a bridge of the structure —*O—CH₂—CH—CH₃ or —*O—CH₂—N—R⁸where the atom marked with * is attached to the carbon atom of A and inwhich R⁸ is hydrogen or methyl; B represents N, C—H, C—F, C—Cl, orC—NH₂; Y represents hydrogen or together with R² may form a bridge ofthe structure —*S—NH— where the atom marked with * represents Y, and Trepresents a radical of the formula

 in which R⁴ represents H, CH₃, C₂H₅, optionally amino-substituted acylhaving 1 to 5 carbon atoms, alkoxycarbonyl, aminocarbonyl,alkylthio-thiocarbonyl and dialkoxyphosphoryl having 1 to 4 carbon atomsin the alkyl moiety; R⁵ represents H, CH₃ or C₂H₅; and R⁶ represents H;or a pharmaceutically useful hydrate, acid addition salt or alkalimetal, alkaline earth metal, silver or guanidinium salt thereof.
 6. Themethod according to claim 4, wherein in the compound of formula (I): R¹represents alkyl having 1 to 4 carbon atoms which is optionally mono- ordisubstituted by fluorine, optionally fluorine-substituted cyclopropyl,phenyl which is optionally mono- or disubstituted cyclopropyl, or phenylwhich is optionally mono- or disubstituted by fluorine; R² representshydroxyl, optionally ethoxycarbonyl-substituted alkoxy having 1 to 4carbon atoms, benzyloxy, allyloxy, or propargyloxy; R³ representshydrogen, amino, hydroxyl, or fluorine; A represents N or C—R⁷ in whichR⁷ represents hydrogen, chlorine, fluorine, OCH₃, OCHF₂, CH₃ or CN orelse together with R¹ may form a bridge of the structure —*O—CH₂—CH—CH₃,or —*O—CH₂—N—CH₃ where the atom marked with * is attached to the carbonatom of A; B represents N, C—H, or C—F; Y represents hydrogen ortogether with R² may form a bridge of the structure —*S—NH— where theatom marked with * represents Y; and T represents a radical of theformula:

 in which R⁴ represents H, CH₃, C₂H₅, optionally amino-substituted acylhaving 1 to 4 carbon atoms or alkoxycarbonyl having 1 to 4 carbon atomsin the alkyl moiety; R⁵ represents H; and R⁶ represents H; or apharmaceutically useful hydrate, acid addition salt or alkali metal,alkaline earth metal, silver or guanidinium salt thereof.
 7. The methodaccording to claim 4, wherein the compound of formula (I) isdiastereomerically pure or enantiomerically pure.
 8. A method oftreating a Heliobacter pylori infection or a gastroduodenal disorderassociated therewith, said method comprising administering to a patientin need thereof an effective amount therefor of the compound accordingto claim 2.